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α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway.

Saraswati S, Kumar S, Alhaider AA - Mol. Cancer (2013)

Bottom Line: However, recently, most of these anticancer drugs have some adverse effects.The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis.Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. saritasaraswati@gmail.com.

ABSTRACT

Background: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.

Methods: We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol.

Results: α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.

Conclusion: α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

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Related in: MedlinePlus

α-santalol interacted with the ATP-binding sites of VEGFR2 kinase domain. (A) Chemical structure of α-santalol. Binding sites of original crystallized bound 0KF and docked α-Santalol ligand (B) Ribbon structure of VEGFR2 protein (PDB-ID: 3VO3) in green colour has been created by Chimera program. (C) Binding site location of both ligands is same as for ATP binding site has been shown surface representation figure-B. Different types of surface colors of both ligands are showing chemical nature of involved heteroatoms. 0KF ligand has Oxygen (in red colour), Nitrogen (in blue colour) and carbon (in grey colour) while α-Santalol contains only Oxygen and carbon heteroatms. (D) 2-dimensional interaction map of α-Santalol and involved amino acids of 3VO3 proteins were calculated by LigPlot Software. Key describes the types of involved interaction and bonds.
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Figure 1: α-santalol interacted with the ATP-binding sites of VEGFR2 kinase domain. (A) Chemical structure of α-santalol. Binding sites of original crystallized bound 0KF and docked α-Santalol ligand (B) Ribbon structure of VEGFR2 protein (PDB-ID: 3VO3) in green colour has been created by Chimera program. (C) Binding site location of both ligands is same as for ATP binding site has been shown surface representation figure-B. Different types of surface colors of both ligands are showing chemical nature of involved heteroatoms. 0KF ligand has Oxygen (in red colour), Nitrogen (in blue colour) and carbon (in grey colour) while α-Santalol contains only Oxygen and carbon heteroatms. (D) 2-dimensional interaction map of α-Santalol and involved amino acids of 3VO3 proteins were calculated by LigPlot Software. Key describes the types of involved interaction and bonds.

Mentions: Angiogenesis is a complex process, which comprises the activation, adhesion, proliferation and transmigration of ECs from pre-existing blood vessels [1]. VEGF is a secreted endothelial cell mitogen that has been shown to induce vasculogenesis and angiogenesis in many organ systems and tumors. VEGF is abundantly produced by hypoxic tumor cells, macrophages and other cells of the immune system [2,3]. Besides affecting vasodilation and vascular permeability, VEGF can induce the expression of proteases and receptors important in cellular invasion and tissue remodeling and is able to prevent endothelial cell apoptosis [2,3]. After proper activation of the endothelial cells, endothelial penetration into new areas of the body is achieved by degradation of the basement membrane by matrix metalloproteinases (MMPs). These extracellular endopeptidases are secreted as zymogens that become activated in the ECM compartment and subsequently selectively degrade components of the ECM [4]. They are produced by a variety of cells, including epithelial cells, fibroblasts, inflammatory cells, and endothelial cells. MMP activity and, hence, angiogenesis is counteracted by the family of tissue inhibitors of metalloproteinase (TIMPs) [5,6]. Since angiogenesis is an event critical to primary tumour growth as well as metastasis, anti-angiogenic therapy is considered a major anti-cancer treatment modality [7]. Although major advances have been made and encouraging clinical results obtained, safer and more effective approaches are required. The identification of new drugs from plants has a long and successful history, and certain proangiogenic and antiangiogenic plant components have been used in traditional medicine system for thousands of years. α-santalol (Figure 1A), a sesquiterpene isolated from Santalum album Linn. has been traditionally used in the treatment of various skin disorders [8]. α-santalol is known to prevent chemically-induced UVB induced skin carcinogenesis in various animal models [9-12]. α-santalol induced apoptosis in prostate cancer cells via activation of caspase-3 and PARP cleavage [13] and human promyelocytic leukemia HL-60 cells [14]. α- santalol induced G2/M phase cell cycle in human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells and up-regulated the expression of p21 and suppressed expressions of mutated p53 in A431 cells [15]. α-santalol exhibited microtubule depolymerization similar to that of vinblastine in UACC-62 melanoma cells [15]. However, its roles in tumor angiogenesis and the involved molecular mechanism are still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro, ex vivo and in vivo. In this study, we demonstrated the antiangiogenic effect of α-santalol on human umbilical vein endothelial cells (HUVECs) in vitro and PC-3 xenograft tumor model in vivo.


α-santalol inhibits the angiogenesis and growth of human prostate tumor growth by targeting vascular endothelial growth factor receptor 2-mediated AKT/mTOR/P70S6K signaling pathway.

Saraswati S, Kumar S, Alhaider AA - Mol. Cancer (2013)

α-santalol interacted with the ATP-binding sites of VEGFR2 kinase domain. (A) Chemical structure of α-santalol. Binding sites of original crystallized bound 0KF and docked α-Santalol ligand (B) Ribbon structure of VEGFR2 protein (PDB-ID: 3VO3) in green colour has been created by Chimera program. (C) Binding site location of both ligands is same as for ATP binding site has been shown surface representation figure-B. Different types of surface colors of both ligands are showing chemical nature of involved heteroatoms. 0KF ligand has Oxygen (in red colour), Nitrogen (in blue colour) and carbon (in grey colour) while α-Santalol contains only Oxygen and carbon heteroatms. (D) 2-dimensional interaction map of α-Santalol and involved amino acids of 3VO3 proteins were calculated by LigPlot Software. Key describes the types of involved interaction and bonds.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
getmorefigures.php?uid=PMC4221991&req=5

Figure 1: α-santalol interacted with the ATP-binding sites of VEGFR2 kinase domain. (A) Chemical structure of α-santalol. Binding sites of original crystallized bound 0KF and docked α-Santalol ligand (B) Ribbon structure of VEGFR2 protein (PDB-ID: 3VO3) in green colour has been created by Chimera program. (C) Binding site location of both ligands is same as for ATP binding site has been shown surface representation figure-B. Different types of surface colors of both ligands are showing chemical nature of involved heteroatoms. 0KF ligand has Oxygen (in red colour), Nitrogen (in blue colour) and carbon (in grey colour) while α-Santalol contains only Oxygen and carbon heteroatms. (D) 2-dimensional interaction map of α-Santalol and involved amino acids of 3VO3 proteins were calculated by LigPlot Software. Key describes the types of involved interaction and bonds.
Mentions: Angiogenesis is a complex process, which comprises the activation, adhesion, proliferation and transmigration of ECs from pre-existing blood vessels [1]. VEGF is a secreted endothelial cell mitogen that has been shown to induce vasculogenesis and angiogenesis in many organ systems and tumors. VEGF is abundantly produced by hypoxic tumor cells, macrophages and other cells of the immune system [2,3]. Besides affecting vasodilation and vascular permeability, VEGF can induce the expression of proteases and receptors important in cellular invasion and tissue remodeling and is able to prevent endothelial cell apoptosis [2,3]. After proper activation of the endothelial cells, endothelial penetration into new areas of the body is achieved by degradation of the basement membrane by matrix metalloproteinases (MMPs). These extracellular endopeptidases are secreted as zymogens that become activated in the ECM compartment and subsequently selectively degrade components of the ECM [4]. They are produced by a variety of cells, including epithelial cells, fibroblasts, inflammatory cells, and endothelial cells. MMP activity and, hence, angiogenesis is counteracted by the family of tissue inhibitors of metalloproteinase (TIMPs) [5,6]. Since angiogenesis is an event critical to primary tumour growth as well as metastasis, anti-angiogenic therapy is considered a major anti-cancer treatment modality [7]. Although major advances have been made and encouraging clinical results obtained, safer and more effective approaches are required. The identification of new drugs from plants has a long and successful history, and certain proangiogenic and antiangiogenic plant components have been used in traditional medicine system for thousands of years. α-santalol (Figure 1A), a sesquiterpene isolated from Santalum album Linn. has been traditionally used in the treatment of various skin disorders [8]. α-santalol is known to prevent chemically-induced UVB induced skin carcinogenesis in various animal models [9-12]. α-santalol induced apoptosis in prostate cancer cells via activation of caspase-3 and PARP cleavage [13] and human promyelocytic leukemia HL-60 cells [14]. α- santalol induced G2/M phase cell cycle in human epidermoid carcinoma A431 cells and p53 wild-type human melanoma UACC-62 cells and up-regulated the expression of p21 and suppressed expressions of mutated p53 in A431 cells [15]. α-santalol exhibited microtubule depolymerization similar to that of vinblastine in UACC-62 melanoma cells [15]. However, its roles in tumor angiogenesis and the involved molecular mechanism are still unknown. Therefore, we examined its anti-angiogenic effects and mechanisms in vitro, ex vivo and in vivo. In this study, we demonstrated the antiangiogenic effect of α-santalol on human umbilical vein endothelial cells (HUVECs) in vitro and PC-3 xenograft tumor model in vivo.

Bottom Line: However, recently, most of these anticancer drugs have some adverse effects.The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis.Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions.

View Article: PubMed Central - HTML - PubMed

Affiliation: Camel Biomedical Research Unit, College of Pharmacy and Medicine, King Saud University, Riyadh, Kingdom of Saudi Arabia. saritasaraswati@gmail.com.

ABSTRACT

Background: VEGF receptor 2 (VEGFR2) inhibitors, as efficient antiangiogenesis agents, have been applied in the cancer treatment. However, recently, most of these anticancer drugs have some adverse effects. Discovery of novel VEGFR2 inhibitors as anticancer drug candidates is still needed.

Methods: We used α-santalol and analyzed its inhibitory effects on human umbilical vein endothelial cells (HUVECs) and Prostate tumor cells (PC-3 or LNCaP) in vitro. Tumor xenografts in nude mice were used to examine the in vivo activity of α-santalol.

Results: α-santalol significantly inhibits HUVEC proliferation, migration, invasion, and tube formation. Western blot analysis indicated that α-santalol inhibited VEGF-induced phosphorylation of VEGFR2 kinase and the downstream protein kinases including AKT, ERK, FAK, Src, mTOR, and pS6K in HUVEC, PC-3 and LNCaP cells. α-santalol treatment inhibited ex vivo and in vivo angiogenesis as evident by rat aortic and sponge implant angiogenesis assay. α-santalol significantly reduced the volume and the weight of solid tumors in prostate xenograft mouse model. The antiangiogenic effect by CD31 immunohistochemical staining indicated that α-santalol inhibited tumorigenesis by targeting angiogenesis. Furthermore, α-santalol reduced the cell viability and induced apoptosis in PC-3 cells, which were correlated with the downregulation of AKT, mTOR and P70S6K expressions. Molecular docking simulation indicated that α-santalol form hydrogen bonds and aromatic interactions within the ATP-binding region of the VEGFR2 kinase unit.

Conclusion: α-santalol inhibits angiogenesis by targeting VEGFR2 regulated AKT/mTOR/P70S6K signaling pathway, and could be used as a potential drug candidate for cancer therapy.

Show MeSH
Related in: MedlinePlus